Transnasal Treatment of Chemokine Analogs for NeuroAIDS

Shu-ichi Okamoto, Burnham Institute for Medical Research, La Jolla
Basic Biomedical Sciences
Innovative, Developmental, Exploratory Award (IDEA)

Effective highly-active antiretroviral therapy (HAART) has helped human immunodeficiency virus (HIV)-infected patients survive longer. However, the inefficient penetrance of HAART drugs into the brain has resulted in an increased prevalence of HIV-associated dementia (HAD). Currently, there is no effective therapy for HAD.

The pathogenesis of HAD is attributable to HIV proteins such as gp120. We and others have demonstrated that gp120 causes its detrimental effects via HIV co-receptors, CXC chemokine receptor 4 (CXCR4) and CC chemokine receptor 5 (CCR5). Thus, these receptors are attractive targets for HAD therapy. Along this line, we developed new peptide inhibitors (termed synthetically and modularly modified (SMM)-chemokine analogs). We here aim to test their efficacy in a HAD animal model. Specifically, we propose to investigate whether transnasal application of SMM-chemokine analogs restores the proliferation of adult neural progenitors in a HAD mouse model which expresses gp120 in the brain.

We recently found a significant decrement in proliferation of adult neural progenitors in gp120/HAD mice similar to that previously observed in the brains of human HAD patients. Adult neurogenesis has been postulated to be important for the processes of learning and memory. Thus, the decrement in adult neurogenesis is, at least in part, relevant to HAD. Importantly, peptides can be delivered into the brain via transnasal application. Furthermore, transnasal administration of SMM-chemokine analogs is associated with non-invasiveness and ease of application that encourage this proposal as a viable strategy for delivering peptide antagonists like SMM-chemokine analogs into patients. Thus, this study proposes to investigate a noninvasive strategy/therapy targeted for HAD patients using a small animal model of HAD.